Durable antimicrobial layer for implantable medical devices

ABSTRACT

An implantable medical device includes a polymer substrate and at least one nanofiber. The polymer substrate includes a surface portion extending into the polymer substrate from a surface of the substrate. The at least one nanofiber includes a first portion and a second portion. The first portion is interpenetrated with the surface portion of the substrate, and mechanically fixed to the substrate. The second portion projects from the surface of the substrate.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to Provisional Application No.62/372,416, filed Aug. 9, 2016, which is herein incorporated byreference in its entirety.

TECHNICAL FIELD

The present invention relates to preventing infections associated withimplantable medical devices. More specifically, the invention relates toantimicrobial, antifouling layers and methods for forming antimicrobial,antifouling layers on surfaces of implantable medical devices.

BACKGROUND

Implantable medical devices may include a housing and a lead or catheterfor delivering therapy to a treatment site within a patient's body. Forexample, a cardiac rhythm management system may include a housing, orpulse generator, containing electronics and a battery; and an electricallead extending from the pulse generator to a treatment site—the heart.In another example, a drug delivery system may include a housing, ordrug delivery pump, containing the pump, a battery, and a supply of thedrug; and a catheter extending from the drug delivery pump to thetreatment site requiring the drug. In some cases, the housing may beinstalled in a subcutaneous pocket within a patient's body.

Implanting a medical device within a patient inherently exposes thepatient to a risk of a nosocomial (e.g., hospital-acquired) infectionassociated with bacteria adhering to the exterior of the medical device.For example, the average nosocomial infection rate associated with theimplantation of cardiovascular implantable electronic devices in 2008was approximately 2.4 percent. In some cases of infection, theimplantable medical device, including a device housing and anyassociated electrical leads or catheters, must be completely removed.Following removal, the infection must be cured and the patient must healenough to tolerate implantation of a replacement medical device. Thecosts of such infections are significant, averaging about $146,000 perinfection. The physical and emotional stress suffered by the patient mayrepresent an even more significant cost.

What is needed is a way to reduce the occurrence of infections which mayresult from implanting a medical device within a patient.

SUMMARY

Example 1 is an implantable medical device including a polymer substrateand at least one nanofiber. The polymer substrate includes a surfaceportion extending into the polymer substrate from a surface of thesubstrate. The at least one nanofiber includes a first portion and asecond portion. The first portion is interpenetrated with the surfaceportion of the substrate, and mechanically fixed to the substrate. Thesecond portion projects from the surface of the substrate

Example 2 is the implantable medical device of Example 1, wherein the atleast one nanofiber has an average diameter ranging from about 100nanometers to about 1,000 nanometers.

Example 3 is the implantable medical device of either of Examples 1 or2, further including a plurality of the nanofibers, wherein at leastsome of the plurality of nanofibers includes the first portion and thesecond portion.

Example 4 is the implantable medical device of any of Examples 1-3,wherein the at least one nanofiber includes at least one of afluoropolymer or a polyurethane.

Example 5 is the implantable medical device of Example 4, wherein the atleast one nanofiber further includes poly(ethylene glycol).

Example 6 is the implantable medical device of any of Examples 1-5,further including a cross-linked poly(ethylene glycol) coatingmechanically linked to the second portion of the at least one nanofiber.

Example 7 is the implantable medical device of Example 6, wherein thecross-linked poly(ethylene glycol) coating includes an initiatorresidue.

Example 8 is the implantable medical device of either of Examples 6 or7, wherein the cross-linked poly(ethylene glycol) coating is bonded tothe second portion of the at least one nanofiber by covalent bonds.

Example 9 is a method of forming an antimicrobial layer on a surface ofa polymer substrate of an implantable medical device. The methodincludes interpenetrating a first portion of at least one nanofiberwithin a surface portion of the substrate, the surface portion extendingfrom the surface into the substrate, the surface portion being in aliquid or semi-liquid state; and solidifying the surface portion,wherein the first portion of the at least one nanofiber is mechanicallyfixed within the surface portion and a second portion of the at leastone nanofiber projects away from the surface.

Example 10 is the method of Example 9, wherein interpenetrating thefirst portion of the at least one nanofiber within the surface portionincludes electro-spinning a nanofiber directly into the surface portion.

Example 11 is the method of Example 9, wherein interpenetrating thefirst portion of the at least one nanofiber within the surface portionincludes electro-spinning the at least one nanofiber onto a core pin ora mandrel and over-molding the surface portion onto the first portion ofthe at least one nanofiber on the core pin or mandrel.

Example 12 is the method of any of Examples 9-11, wherein solidifyingthe surface portion includes cross-linking the polymer substrate aroundthe first portion of the at least one nanofiber.

Example 13 is the method of any of Examples 9-12, further includingcoating the second portion of the at least one nanofiber with apoly(ethylene glycol) and cross-linking the poly(ethylene glycol)coating to mechanically link the poly(ethylene glycol) to the secondportion of the at least one nanofiber.

Example 14 is the method of Example 13, wherein the poly(ethyleneglycol) includes at least one of an ultraviolet initiator and a thermalinitiator, and cross-linking the poly(ethylene glycol) coating includesexposing the ultraviolet initiator and the thermal initiator toultraviolet radiation or heat, respectively.

Example 15 is the method of either of Examples 13-14, further includingexposing the second portion of the plurality of nanofibers and thepoly(ethylene glycol) coating to an argon-containing plasma tocovalently bond the cross-linked poly(ethylene glycol) coating to thesecond portion of the plurality of nanofibers.

Example 16 is an implantable medical device including a polymersubstrate and at least one nanofiber. The polymer substrate includes asurface portion extending into the polymer substrate from a surface ofthe substrate. The at least one nanofiber includes a first portion and asecond portion. The first portion is interpenetrated with the surfaceportion of the substrate, and mechanically fixed to the substrate. Thesecond portion projects from the surface and forms an antimicrobiallayer on the surface.

Example 17 is the implantable medical device of Example 16, wherein theat least one nanofiber has an average diameter ranging from about 100nanometers to about 1,000 nanometers.

Example 18 is the implantable medical device of either of Examples 16 or17, further including a plurality of the nanofibers, wherein at leastsome of the plurality of nanofibers includes the first portion and thesecond portion.

Example 19 is the implantable medical device of any of Examples 16-18,wherein the at least one nanofiber includes at least one of afluoropolymer or a polyurethane.

Example 20 is the implantable medical device of any of Examples 16-18,wherein the at least one nanofiber further includes poly(ethyleneglycol).

Example 21 is the implantable medical device of any of Examples 16-20,further including a cross-linked poly(ethylene glycol) coatingmechanically linked to the second portion of the at least one nanofiber.

Example 22 is the implantable medical device of Example 21, wherein thecross-linked poly(ethylene glycol) coating includes an initiatorresidue.

Example 23 is the implantable medical device of either of Examples 21 or22, wherein the cross-linked poly(ethylene glycol) coating is bonded tothe second portion of the at least one nanofiber by covalent bonds.

Example 24 is an implantable medical device including a polymersubstrate and a plurality of nanofibers. The polymer substrate includesa surface and a surface portion extending from the surface to a depthinto the polymer substrate. The plurality of nanofibers include a firstportion and a second portion. The first portion is interpenetrated withthe surface portion of the substrate, and mechanically fixed to thesubstrate. The second portion projects from the surface and forms anantimicrobial layer on the surface.

Example 25 is the implantable medical device of Example 24, wherein thenanofibers have diameters ranging from about 100 nanometers to about1,000 nanometers.

Example 26 is the implantable medical device of either of Examples 24 or25, further including a cross-linked poly(ethylene glycol) coatingmechanically linked to the second portion.

Example 27 is the implantable medical device of Example 26, wherein thecross-linked poly(ethylene glycol) coating includes an initiatorresidue.

Example 28 is the implantable medical device of either of Examples 26 or27, wherein the cross-linked poly(ethylene glycol) coating is bonded tothe second portion by covalent bonds.

Example 29 is a method of forming an antimicrobial layer on a surface ofa polymer substrate of an implantable medical device. The methodincludes interpenetrating a first portion of at least one nanofiberwithin a surface portion of the substrate, the surface portion extendingfrom the surface into the substrate, the surface portion being in aliquid or semi-liquid state; and solidifying the surface portion,wherein the first portion of the at least one nanofiber is mechanicallyfixed within the surface portion and a second portion of the at leastone nanofiber projects away from the surface to form the antimicrobiallayer.

Example 30 is the method of Example 29, wherein interpenetrating thefirst portion of the at least one nanofiber within the surface portionincludes electro-spinning a nanofiber directly into the surface portion.

Example 31 is the method of Example 29, wherein interpenetrating thefirst portion of the at least one nanofiber within the surface portionincludes electro-spinning the at least one nanofiber onto a core pin ora mandrel and over-molding the surface portion onto the first portion ofthe at least one nanofiber on the core pin or mandrel.

Example 32 is the method of any of Examples 29-31, wherein solidifyingthe surface portion includes cross-linking the polymer substrate aroundthe first portion of the at least one nanofiber.

Example 33 is the method of any of Examples 29-32, further includingcoating the second portion of the at least one nanofiber with apoly(ethylene glycol) and cross-linking the poly(ethylene glycol)coating to mechanically link the poly(ethylene glycol) to the secondportion of the at least one nanofiber.

Example 34 is the method of Example 33, wherein the poly(ethyleneglycol) includes at least one of an ultraviolet initiator and a thermalinitiator, and cross-linking the poly(ethylene glycol) coating includesexposing the ultraviolet initiator and the thermal initiator toultraviolet radiation or heat, respectively.

Example 35 is the method of either of Examples 33 or 34, furtherincluding exposing the second portion of the plurality of nanofibers andthe poly(ethylene glycol) coating to an argon-containing plasma tocovalently bond the cross-linked poly(ethylene glycol) coating to thesecond portion of the plurality of nanofibers.

While multiple embodiments are disclosed, still other embodiments of thepresent invention will become apparent to those skilled in the art fromthe following detailed description, which shows and describesillustrative embodiments of the invention. Accordingly, the drawings anddetailed description are to be regarded as illustrative in nature andnot restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of exemplary implantable medicaldevices including a medical electrical lead and a suture sleeve.

FIG. 2 is a schematic cross-sectional view of a portion of theimplantable medical electrical lead FIG. 1.

FIG. 3 is an enlarged schematic cross-sectional view of a portion of thelead body 116 of FIG. 2 illustrating an antimicrobial layer on an outersurface of a medical electrical lead, according to some embodiments.

FIG. 4 is an enlarged schematic cross-sectional view of a portion of thelead body 116 of FIG. 2 illustrating an antimicrobial layer on an outersurface of a medical electrical lead, according to some embodiments.

FIGS. 5A-5C are enlarged schematic cross-sectional views illustrating anantimicrobial layer and its formation on a portion of the suture sleeveof FIG. 2.

FIG. 6 is an enlarged schematic cross-sectional view of a portion of thesuture sleeve of FIG. 2, illustrating an antimicrobial layer on asurface of the suture sleeve, according to some embodiments.

FIGS. 7A and 7B are cross-sectional micrographs of a suture sleeveillustrating an antimicrobial layer on a surface of the suture sleeve,according to embodiments.

While the invention is amenable to various modifications and alternativeforms, specific embodiments have been shown by way of example in thedrawings and are described in detail below. The intention, however, isnot to limit the invention to the particular embodiments described. Onthe contrary, the invention is intended to cover all modifications,equivalents, and alternatives falling within the scope of the inventionas defined by the appended claims.

DETAILED DESCRIPTION

A more complete understanding of the present invention is available byreference to the following detailed description of numerous aspects andembodiments of the invention. The detailed description of the inventionwhich follows is intended to illustrate but not limit the invention.

In accordance with various aspects of the disclosure, a medical deviceis defined as “an implantable medical device” if it is totally or partlyintroduced, surgically or medically, into the human body or by medicalintervention into a natural orifice, and which is intended to remainafter the procedure. Exemplary implantable medical devices can include amedical electrical lead or a suture sleeve, as discussed below. However,it is understood that the various embodiments can be implemented in anyimplantable medical device implanted in a patient. For example,embodiments may be employed with a subcutaneously-implanted implantablecardioverter-defibrillator (ICD) housing and lead system. Such a systemmay include a housing implanted in a subcutaneous pocket in a patient'schest, and a lead traversing a subcutaneous path from the subcutaneouspocket to the anterior precordial region. Embodiments may be employedwithin the subcutaneous pocket containing the ICD housing and along thesubcutaneous path traversed by the lead. Other such implantable medicaldevices include, without limitation, cardioverter-defibrillator orcardiac resynchronization therapy devices, leadless pacing devices,implantable cardiac monitors, endocardial leads, epicardial leads,neurostimulation systems such as spinal cord stimulation or deep brainstimulation device housings and associated leads, implantable drugpumps, ostomy ports, and urology catheters, to name a few.

FIG. 1 is a schematic illustration of exemplary implantable medicaldevices including a medical electrical lead 110 and a suture sleeve 122.FIG. 1 shows a cardiac rhythm management (CRM) system 100 for deliveringand/or receiving electrical pulses or signals to stimulate, shock,and/or sense a heart 102. The CRM system 100 can include a pulsegenerator 105 and the medical electrical lead 110. The pulse generator105 includes a source of power as well as an electronic circuitryportion. The pulse generator 105 may be a battery-powered device whichgenerates a series of timed electrical discharges or pulses. The pulsegenerator 105 may be implanted into a subcutaneous pocket made in thewall of the chest. Alternatively, the pulse generator 105 may be placedin a subcutaneous pocket made in the abdomen, or in another location. Itshould be noted that while the medical electrical lead 110 isillustrated for use with a heart 102, the medical electrical lead 110 issuitable for other forms of electrical stimulation/sensing as well.

In some embodiments, the medical electrical lead 110 extends from aproximal end 112, where it is coupled with the pulse generator 105 to adistal end 114, which is coupled with a portion of the heart 102, whenimplanted or otherwise coupled therewith. The medical electrical lead110 includes a lead body 116 extending generally from the proximal end112 to the distal end 114. The lead body 116 may be a tubular structure.Disposed along a portion of the medical electrical lead 110, for examplenear the distal end 114, may be at least one electrode 118 whichelectrically couples the medical electrical lead 110 with the heart 102.At least one electrical conductor 120 (FIG. 2) may be disposed withinthe lead body 116 and extend generally from the proximal end 112 to thedistal end 114. The at least one electrical conductor 120 electricallyconnects the electrode 118 with the proximal end 112 of the medicalelectrical lead 110 to couple the electrode 118 to the pulse generator105. The electrical conductor 120 carries electrical current and pulsesbetween the pulse generator 105 and the electrode 118, and to and fromthe heart 102.

The medical electrical lead 110 can be secured in place by the suturesleeve 122. Migration and dislodgment of the medical electrical lead 110may be discouraged by securing the suture sleeve 122 about the lead body116 and suturing the suture sleeve 122 to the patient's tissue.

FIG. 2 is a schematic cross-sectional view of a portion of theimplantable medical electrical lead 110 of FIG. 1 showing the suturesleeve 122 about the lead body 116. In the embodiment shown in FIG. 2,the lead body 116 is a tubular structure including an outer surface 124,and an inner surface 126. The inner surface 126 defines a lead lumen128. The electrical conductor 120 extends through the lead lumen 128from the proximal end 112 to the electrode 118 (FIG. 1). The suturesleeve 122 includes an outer surface 130 and an inner surface 132. Inthe embodiment of FIG. 2, the suture sleeve 122 also includes at leastone suture groove 134 (three shown) in the outer surface 130 extendingaround the circumference of the suture sleeve 122. The inner surface 132defines a suture sleeve lumen 136 extending the length of the suturesleeve 122. A diameter of the suture sleeve lumen 136 is greater than adiameter of the lead body 116 such that the suture sleeve lumen 136 maybe moved along the lead body 116 to a position adjacent to tissuesuitable for attachment. Once the suture sleeve lumen 136 is positionedadjacent to tissue, sutures (not shown) may be tightly wrapped aroundthe suture sleeve 122 in the suture grooves 134 and sutured to thepatient's tissue. The tightly wrapped sutures in the suture grooves 134can compress the inner surface 132 of the suture sleeve 122 adjacent tothe suture grooves 134 against the outer surface 124 of the lead body116, securing the lead body 116 within the suture sleeve 122.

The lead body 116 and the suture sleeve 122 include any suitablebiostable, biocompatible polymer, such as a silicone or a polyurethane.The lead body 116 can be formed by extruding or by molding. The suturesleeve 122 can also be formed by molding. The lead body 116 and thesuture sleeve 122 are exemplary polymer substrates.

The outer surface 124 of the lead body 116 can include various marks andsurface features (not shown). For example, lead bodies may be extrudedand the extrusion process may produce marks and surface features. It hasbeen found that the marks and surface features may provide a safe havenfor bacteria to colonize the surface of the lead body 116, leading topocket infections, bacteremia, or endocarditis. Similarly, the outersurface 130 and the inner surface 132 of the suture sleeve 122 can alsoinclude various marks and surface features suitable for the colonizationof bacteria. Bacteria growth can be particularly aggressive on the outersurface 124 of lead body 116 under the edge of the suture sleeve 122 insuture sleeve lumen 136.

FIG. 3 is an enlarged schematic cross-sectional view of a portion of thelead body 116 of FIG. 2 illustrating an antimicrobial layer on the outersurface 124 of a medical electrical lead 110, according to someembodiments. As shown in FIG. 3, the lead body 116 includes at least onenanofiber 138. The nanofiber 138 includes a first portion 140 and asecond portion 142. The first portion 140 is embedded in, orinterpenetrated with, a surface portion 144 of the lead body 116. Thesurface portion 144 extends from the outer surface 124 into the leadbody 116 to a depth D. The second portion 142 projects from the outersurface 124. The first portion 140 is mechanically fixed to the outersurface 124 by virtue of the embedded, interpenetrating structure. Ithas been found that the second portion 142 of the nanofiber 138projecting from the outer surface 124 presents a surface morphology thatis less amenable for bacterial adhesion than the outer surface 124without the nanofiber 138. By discouraging adhesion of bacteria to theouter surface 124, the second portion 142 forms an antimicrobial layerthat may inhibit bacterial colonization. The antimicrobial layer formedby the second portion 142 is durable because the nanofiber 138 ismechanically fixed to the surface portion 144 by the first portion 140.

In some embodiments, the nanofiber 138 winds its way into and out of thesurface portion 144 to define the first portion 140 and the secondportion 142. Such a structure can produce loops of nanofibers embeddedin the surface portion 144 which may help mechanically fix the firstportion 140 to the surface portion 144. In the embodiment shown in FIG.3, the at least one nanofiber 138 includes a plurality of nanofibers138, winding their way into and out of the surface portion 144 withtheir own first portions 140 interpenetrated with the surface portion144, and second portions 142 projecting form the outer surface 124.

In some embodiments, the depth D to which the surface portion 144extends may be as small as about 10 microns, about 20 microns, or about30 microns, or as great as about 50 microns, about 60 microns, or about125 microns, or may extend an amount within any range defined betweenany pair of the foregoing values. In some embodiments, the depth D mayrange from about 10 microns to about 125 microns, about 20 microns toabout 60 microns, or about 30 microns to about 50 microns. In someembodiments, the depth D may be about 40 microns.

In some embodiments, the at least one nanofiber 138 can have an averagediameter as small as about 100 nanometers, about 200 nanometers, orabout 400 nanometers, or as large as about 600 nanometers, about 800nanometers, or about 1,000 nanometers. In some embodiments, the averagediameter of the at least one nanofiber 138 can range from about 100nanometers to about 1,000 nanometers, about 200 nanometers to about 800nanometers, or about 400 nanometers to about 600 nanometers. In someembodiments, the at least one nanofiber 138 can have a diameter of about500 nanometers. In embodiments in which the at least one nanofiber 138includes a plurality of nanofibers 138, the nanofiber diameter size maybe determined by measuring the average diameter of the nanofibers.

The at least one nanofiber 138 may include any suitable biostable,biocompatible polymer that can be formed into nanofibers. In someembodiments in which the nanofiber 138 is formed by electro-spinning,the nanofiber 138 can include a fluoropolymer, such aspolytetrafluoroethylene (PTFE), polyvinlyidene fluoride (PVDF), orpoly(vinylidene fluoride-co-hexafluoropropene) (PVDF-HPV); apolyurethane, such as polyether polyurethane, polycarbonatepolyurethane, or polyisobutylene-polyurethane (PIB-PUR); orstyrene-isobutylene-styrene (SIBS).

In some embodiments, the at least one nanofiber 138 can include asuitable hydrophilic polymer, such as poly(ethylene glycol), blendedwith the nanofiber polymer (e.g., the fluoropolymer, the polyurethane,or the SIBS). That is, the nanofiber 138 may be formed from a blend ofthe nanofiber polymer and poly(ethylene glycol). In such embodiments,exposing the nanofiber 138 to a plasma that contains argon cancross-link the poly(ethylene glycol) and covalently bond thepoly(ethylene glycol) to the nanofiber polymer, as described below inreference to FIG. 4. The poly(ethylene glycol) in the nanofiber 138 iscross-linked so that it is biostable, and is covalently bonded to thenanofiber polymer so that it is durably attached to the nanofiberpolymer to form the nanofiber 138. The presence of the cross-linkedpoly(ethylene glycol) in the nanofiber 138 may further discouragebacterial adhesion by making the nanofiber 138 hydrophilic, increasingthe antimicrobial, anti-fouling effect of the second portion 142.

In some embodiments, the antimicrobial layer is formed on the outersurface 124 of the lead body 116 by interpenetrating the first portion140 of the at least one nanofiber 138 within the surface portion 144while the surface portion 144 is in a liquid or semi-liquid state, andthen solidifying the surface portion 144 with the second portion 142projecting away from the outer surface 124. In some embodiments in whichthe lead body 116 is made of a thermoset polymer, such as a silicone,the nanofiber 138 can interpenetrate the surface portion 144 while thepolymer is in a liquid or semi-liquid state before it solidifies bycuring, or cross-linking portions of the polymer around portions of thefirst portion 140. In other embodiments in which the lead body 116 ismade of a thermoplastic polymer, the nanofiber 138 can interpenetratethe surface portion 144 while the polymer is in a liquid or semi-liquidstate created by heating the polymer to melt or soften the surfaceportion 144, or by dissolution of the surface portion 144 in a suitablesolvent. For example, when the lead body 116 is formed of apolyurethane, tetrahydrofuran or dimethylformamide may be used to softenthe surface portion 144, creating a semi-liquid state. Once the firstportion 140 of the nanofiber 138 has interpenetrated the surface portion144, the surface portion 144 can be cooled, or the solvent permitted toevaporate, to solidify the surface portion 144, mechanically fixing thefirst portion 140 within the surface portion 144.

In some embodiments, interpenetration the first portion 140 of thenanofiber 138 within the surface portion 144 includes electro-spinning ananofiber directly into the surface portion 144 while the surfaceportion 144 is in a liquid or semi-liquid state.

FIG. 4 is an enlarged schematic cross-sectional view of a portion of thelead body 116 of FIG. 2 illustrating an antimicrobial layer on the outersurface 124 of a medical electrical lead 110, according to someembodiments. The embodiment shown in FIG. 4 is similar or identical tothe embodiment shown in FIG. 3, except that it includes a cross-linkedpoly(ethylene glycol) coating 146 on the second portion 142. Thepoly(ethylene glycol) coating 146 is cross-linked around and between atleast some of the second portion 142 so that it is mechanically linkedto the at least one nanofiber 138. The poly(ethylene glycol) coating 146is also biostable because it is cross-linked. The presence of thepoly(ethylene glycol) coating 146 around the nanofibers 138 may furtherdiscourage bacterial adhesion by providing a hydrophilic, anti-foulingcoating on the second portion 142 of the nanofibers 138. It has beenfound that the combination of the surface morphology of the secondportion 142 and the hydrophilic, cross-linked poly(ethylene glycol)coating 146 provides a durable, antimicrobial, anti-fouling layer. Theantimicrobial layer formed by the second portion 142 is durable because,as noted above, the at least one nanofiber 138 is mechanically fixed tothe surface portion 144 by the first portion 140 and because thepoly(ethylene glycol) coating 146 is mechanically fixed to the secondportion 142.

In the embodiment of FIG. 4, the second portion 142 of the nanofiber 138can be formed as described above in reference to FIG. 3, and coated withpoly(ethylene glycol) in a liquid state. In some embodiments, coatingthe second portion 142 with the poly(ethylene glycol) can includedipping the outer surface 124 into poly(ethylene glycol) that is in aliquid state. In other embodiments, coating the second portion 142 withthe poly(ethylene glycol) can include spraying liquid poly(ethyleneglycol) onto the outer surface 124.

After coating the second portion 142 with the poly(ethyhlene glycol),the poly(ethylene glycol) is cross-linked to mechanically link thepoly(ethylene glycol) to the second portion 142 and form thecross-linked poly(ethylene glycol) coating 146. In some embodiments, thepoly(ethylene glycol) can include a radical initiator compound thatgenerates free radicals when exposed to energy, such as ultravioletradiation or heat. The free radicals can initiate cross-linking of thepoly(ethylene glycol). Examples of suitable UV initiator compoundsinclude (4-bromophenyl)diphenylsulfonium triflate,(4-fluorophenyl)diphenylsulfonium triflate,(4-iodophenyl)diphenylsulfonium triflate,(4-methoxyphenyl)diphenylsulfonium triflate,(4-methylphenyl)diphenylsulfonium triflate, (4-methylthiophenyl)methylphenyl sulfonium triflate, (4-phenoxyphenyl)diphenylsulfonium triflate,(4-phenylthiophenyl)diphenylsulfonium triflate,(4-tert-butylphenyl)diphenylsulfonium triflate,(cumene)cyclopentadienyliron(II) hexafluorophosphate,(tert-butoxycarbonylmethoxynaphthyl)-diphenylsulfonium triflate,1-naphthyl diphenylsulfonium triflate,2-(4-methoxystyryl)-4,6-bis(trichloromethyl)-1,3,5-triazine,bis(4-tert-butylphenyl)iodonium perfluoro-1-butanesulfonate,bis(4-tert-butylphenyl)iodonium p-toluenesulfonate,bis(4-tert-butylphenyl)iodonium triflate,boc-methoxyphenyldiphenylsulfonium triflate, diphenyliodoniumhexafluorophosphate, diphenyliodonium nitrate, diphenyliodoniumperfluoro-1-butanesulfonate, diphenyliodonium p-toluenesulfonate,diphenyliodonium triflate, N-hydroxy-5-norbornene-2,3-dicarboximideperfluoro-1-butanesulfonate, N-hydroxynaphthalimide triflate,triarylsulfonium hexafluoroantimonate salts, triphenylsulfoniumperfluoro-1-butanesufonate, triphenylsulfonium triflate,tris(4-tert-butylphenyl)sulfonium perfluoro-1-butanesulfonate, andtris(4-tert-butylphenyl)sulfonium triflate. Examples of suitable thermalinitiator compounds include azobisisobutyronitrile (AIBN), dibenzoylperoxide, N-benzyl pyridinium bromide, N-benzyl o-cyano pyridiniumbromide, N-benzyl p-cyanopyridinium bromide, N-benzyl N, N-dimethylanilinium bromide, and benzyl triphenyl phosphonium bromide.

Thus, in some embodiments, the cross-linked poly(ethylene glycol) 146can include a residue of a cross-linking initiator. For example, theinitiator residue may include, for example, a residue of any of theultraviolet initiators or the thermal initiators describe above.

In some embodiments, the cross-linked poly(ethylene glycol) 146 can becovalently bonded to the second portion 142 of the nanofiber 138, inaddition to being mechanically fixed to the second portion 142. In suchembodiments, the poly(ethylene glycol) 146 is both chemically andmechanically fixed to the second portion 142. In such embodiments,forming the antimicrobial layer can include exposing the second portion142 and the poly(ethylene glycol) 146 to a plasma that contains argon.Free radicals formed by the argon-containing plasma produce reactivesites for covalent bonding of the poly(ethylene glycol) 146 to thesecond portion 142 of the at least one nanofiber 138. Theargon-containing plasma does not include oxygen, as the oxygen has beenfound to deteriorate the nanofiber 138. In some embodiments, theargon-containing plasma can produced from a flow of argon gas at apressure of about 250 mTorr and an applied radio-frequency power ofabout 200 Watts. The second portion 142 and the nanofiber 138 can beexposed to the plasma for a time ranging from about 60 seconds to about180 seconds.

In some embodiments, the free radicals generated by exposure to theargon-containing plasma not only provide reactive sites for covalentbonding of the poly(ethylene glycol) 146 to the second portion 142, butmay also provide free radicals for the cross-linking of thepoly(ethylene glycol) to form the poly(ethylene glycol) coating 146. Insuch embodiments, there may be no need for an ultraviolet initiator or athermal initiator, and no initiator residues present in the cross-linkedpoly(ethylene glycol) coating 146.

Although the embodiments described above employ poly(ethylene glycol) asthe hydrophilic polymer, other suitable hydrophilic polymers can includepolyvinylpyrrolidone (PVP), poly(2-methyl-2-oxazoline),poly(2-ethyl-2-oxazoline, poly(ethylene glycol) methacrylate, andhydroxypropyl cellulose.

Although the embodiments described above are directed to anantimicrobial layer formed on the outer surface 124 of the lead body116, it is understood that the embodiments described above may also beapplied to the outer surface 130 of the suture sleeve 122.

The description above in reference to FIGS. 3 and 4 described anantimicrobial layer and its formation on the outer surface 124 of thelead body 116. FIGS. 5A-5C are enlarged schematic cross-sectional viewsillustrating an antimicrobial layer and its formation on the innersurface 132 of the suture sleeve 122. FIG. 5A shows a core pin ormandrel 148 and at least one nanofiber 150 disposed onto the core pin ormandrel 148. The nanofiber 150 can be similar or identical to thenanofiber 138 described above in reference to FIGS. 3 and 4. The atleast one nanofiber 150 can be electro-spun onto the core pin or mandrel148. The core pin or mandrel 148 can be rotated while the nanofiber 150is electro-spun onto the core pin or mandrel 148.

After the a least one nanofiber 150 is formed onto the core pin ormandrel 148, the nanofiber 150 and the core pin or mandrel 148 can beover-molded to form the suture sleeve 122 with inner surface 132, asshown in FIG. 5B. For example, the suture sleeve 122 can be made ofsilicone, in which case liquid silicone rubber is injected into a mold(not shown) containing the core pin or mandrel 148 and the nanofiber150. The liquid silicone rubber does not fully penetrate through thenanofiber 150 to the core pin or mandrel 148 because of its relativelyhigh viscosity and the relatively small spaces formed amongst thenanofiber 150 as it is electro spun onto the core pin or mandrel 148.Thus, the inner surface 132 is may be spaced apart from the core pin ormandrel 148. The nanofiber 150 includes a first portion 152 and a secondportion 154. The first portion 152 is embedded in, or interpenetratedwith, a surface portion 156 of the suture sleeve 122. The surfaceportion 156 extends from the inner surface 132 into the suture sleeve122 to a depth D. The second portion 154 projects from the inner surface132. The first portion 152 is mechanically fixed to the inner surface132 by virtue of the embedded, interpenetrating structure.

After the silicone cross-links or cures, the core pin or mandrel 148 canbe removed, as shown in FIG. 5C. As with the embodiment described abovein reference to FIGS. 3 and 4, it has been found that the second portion154 of the nanofiber 150 projecting from the inner surface 132 presentsa surface morphology that is less amenable for bacterial adhesion thanthe inner surface 132 without the nanofiber 150. By discouragingadhesion of bacteria to the inner surface 132, the second portion 154forms an antimicrobial layer that may inhibit bacterial colonization.The antimicrobial layer formed by the second portion 154 is durablebecause the nanofiber 150 is mechanically fixed to the surface portion156 by the first portion 152.

FIG. 6 is an enlarged schematic cross-sectional view of a portion of theinner surface 132 of the suture sleeve 122 of FIG. 2, illustrating anantimicrobial layer on a surface of an implantable device, according tosome embodiments. The embodiment shown in FIG. 6 is similar or identicalto the embodiment shown in FIG. 5C, except that it includes across-linked poly(ethylene glycol) coating 158 on the second portion154. The poly(ethylene glycol) coating 158 is cross-linked around andbetween at least some of the second portion 154 so that it ismechanically linked to the at least one nanofiber 150. The poly(ethyleneglycol) coating 146 is also biostable because it is cross-linked. Thepresence of the poly(ethylene glycol) coating 146 around the nanofiber150 may further discourage bacterial adhesion by providing ahydrophilic, anti-fouling coating on the second portion 154 of thenanofiber 150. It has been found that the combination of the surfacemorphology of the second portion 154 and the hydrophilic, cross-linkedpoly(ethylene glycol) coating 158 provides a durable, antimicrobial,anti-fouling layer. The antimicrobial layer formed by the second portion154 is durable because, as noted above, the at least one nanofiber 150is mechanically fixed to the surface portion 156 by the first portion152 and because the poly(ethylene glycol) coating 158 is mechanicallyfixed to the second portion 154.

In the embodiment of FIG. 6, the second portion 154 of the nanofiber 150can be formed as described above in reference to FIGS. 5A-5C, and coatedwith poly(ethylene glycol) in a liquid state. In some embodiments,coating the second portion 154 with the poly(ethylene glycol) caninclude dipping the inner surface 132 into poly(ethylene glycol) that isin a liquid state. In other embodiments, coating the second portion 154with the poly(ethylene glycol) can include spraying liquid poly(ethyleneglycol) onto the inner surface 132.

After coating the second portion 154 with the poly(ethyhlene glycol),the poly(ethylene glycol) is cross-linked to mechanically link thepoly(ethylene glycol) to the second portion 154 and form thecross-linked poly(ethylene glycol) coating 158. The poly(ethyleneglycol) 158 can be cross-linked as described above for the poly(ethyleneglycol) 146 in reference to FIGS. 3 and 4. Thus, in some embodiments,the cross-linked poly(ethylene glycol) 158 can include a residue of across-linking initiator.

In some embodiments, the cross-linked poly(ethylene glycol) 158 can becovalently bonded to the second portion 154 of the nanofiber 150, inaddition to being mechanically fixed to the second portion 154. In suchembodiments, the poly(ethylene glycol) 158 is both chemically andmechanically fixed to the second portion 154. In such embodiments,forming the antimicrobial layer can include exposing the second portion154 and the poly(ethylene glycol) 158 to a plasma that contains argon.Free radicals formed by the argon-containing plasma produce reactivesites for covalent bonding of the poly(ethylene glycol) 158 to thesecond portion 154 of the nanofiber 150. The argon-containing plasmadoes not include oxygen, as the oxygen has been found to deteriorate thenanofiber 150. In some embodiments, the argon-containing plasma canproduced from a flow of argon gas at a pressure of about 250 mTorr andan applied radio-frequency power of about 200 Watts. The second portion154 and the nanofiber 150 can be exposed to the plasma for a timeranging from about 60 seconds to about 180 seconds.

In some embodiments, the free radicals generated by exposure to theargon-containing plasma not only provide reactive sites for covalentbonding of the poly(ethylene glycol) 158 to the second portion 154, butmay also provide free radicals for the cross-linking of thepoly(ethylene glycol) to form the poly(ethylene glycol) coating 158. Insuch embodiments, there may be no need for an ultraviolet initiator or athermal initiator, and no initiator residues present in the cross-linkedpoly(ethylene glycol) coating 158.

FIGS. 7A and 7B are cross-sectional micrographs of the suture sleeve 122illustrating the inner surface 132 as well as the first portion 152 andthe second portion 154 of the at least one nanofiber 150. In the exampleshown in FIGS. 7A and 7B, the suture sleeve 122 is made of silicone, theat least one nanofiber 150 is made of PVDF, and the second portion 154is coated with poly(ethylene glycol) having an average molecular weightof about 400 grams/mole. FIGS. 7A and 7B are at a magnification of about4,000×. FIG. 7A was taken under color optical illumination to moreclearly show the interpenetration of the first portion 152 with theinner surface 132 of the suture sleeve 122. FIG. 7B was taken underlaser illumination to more clearly show the second portion 154projecting from the inner surface 132.

In the embodiments described above, the poly(ethylene glycol) may be ahydroxy-terminated poly(ethylene glycol). In other embodiments, thepoly(ethylene glycol) may be terminated by a different functional groupthat may aid in cross-linking of the poly(ethylene glycol), such as amethacrylate group.

Various modifications and additions can be made to the exemplaryembodiments discussed without departing from the scope of the presentinvention. For example, while the embodiments described above refer toparticular features, the scope of this invention also includesembodiments having different combinations of features and embodimentsthat do not include all of the described features. Accordingly, thescope of the present invention is intended to embrace all suchalternatives, modifications, and variations as fall within the scope ofthe claims, together with all equivalents thereof.

We claim:
 1. An implantable medical device comprising: a polymersubstrate including a surface portion extending into the polymersubstrate from a surface of the substrate; and at least one nanofiberincluding: a first portion interpenetrated with the surface portion ofthe substrate, and mechanically fixed to the substrate; and a secondportion projecting from the surface and forming an antimicrobial layeron the surface.
 2. The implantable medical device of claim 1, whereinthe at least one nanofiber has an average diameter ranging from about100 nanometers to about 1,000 nanometers.
 3. The implantable medicaldevice of claim 1, further including a plurality of the nanofibers,wherein at least some of the plurality of nanofibers includes the firstportion and the second portion.
 4. The implantable medical device ofclaim 3, wherein the at least one nanofiber includes at least one of afluoropolymer or a polyurethane.
 5. The implantable medical device ofclaim 4, wherein the at least one nanofiber further includespoly(ethylene glycol).
 6. The implantable medical device of claim 1,further including a cross-linked poly(ethylene glycol) coatingmechanically linked to the second portion of the at least one nanofiber.7. The implantable medical device of claim 6, wherein the cross-linkedpoly(ethylene glycol) coating includes an initiator residue.
 8. Theimplantable medical device of claim 6, wherein the cross-linkedpoly(ethylene glycol) coating is bonded to the second portion of the atleast one nanofiber by covalent bonds.
 9. An implantable medical devicecomprising: a polymer substrate including: a surface; and a surfaceportion extending from the surface to a depth into the polymersubstrate; and a plurality of nanofibers, wherein at least some of thenanofibers include: a first portion interpenetrated with the surfaceportion of the substrate, and mechanically fixed to the substrate; and asecond portion projecting from the surface and forming an antimicrobiallayer on the surface.
 10. The implantable medical device of claim 9,wherein the nanofibers have diameters ranging from about 100 nanometersto about 1,000 nanometers.
 11. The implantable medical device of claim9, further including a cross-linked poly(ethylene glycol) coatingmechanically linked to the second portion.
 12. The implantable medicaldevice of claim 11, wherein the cross-linked poly(ethylene glycol)coating includes an initiator residue.
 13. The implantable medicaldevice of claim 11, wherein the cross-linked poly(ethylene glycol)coating is bonded to the second portion by covalent bonds.
 14. A methodof forming an antimicrobial layer on a surface of a polymer substrate ofan implantable medical device, the method comprising: interpenetrating afirst portion of at least one nanofiber within a surface portion of thesubstrate, the surface portion extending from the surface into thesubstrate, the surface portion being in a liquid or semi-liquid state;and solidifying the surface portion, wherein the first portion of the atleast one nanofiber is mechanically fixed within the surface portion anda second portion of the at least one nanofiber projects away from thesurface to form the antimicrobial layer.
 15. The method of claim 14,wherein interpenetrating the first portion of the at least one nanofiberwithin the surface portion includes electro-spinning a nanofiberdirectly into the surface portion.
 16. The method of claim 14, whereininterpenetrating the first portion of the at least one nanofiber withinthe surface portion includes: electro-spinning the at least onenanofiber onto a core pin or a mandrel; and over-molding the surfaceportion onto the first portion of the at least one nanofiber on the corepin or mandrel.
 17. The method of claim 14, wherein solidifying thesurface portion includes cross-linking the polymer substrate around thefirst portion of the at least one nanofiber.
 18. The method of claim 14,further including: coating the second portion of the at least onenanofiber with a poly(ethylene glycol); and cross-linking thepoly(ethylene glycol) coating to mechanically link the poly(ethyleneglycol) to the second portion of the at least one nanofiber.
 19. Themethod of claim 18, wherein the poly(ethylene glycol) includes at leastone of an ultraviolet initiator and a thermal initiator, andcross-linking the poly(ethylene glycol) coating includes exposing theultraviolet initiator and the thermal initiator to ultraviolet radiationor heat, respectively.
 20. The method of claim 18, further includingexposing the second portion of the plurality of nanofibers and thepoly(ethylene glycol) coating to an argon-containing plasma tocovalently bond the cross-linked poly(ethylene glycol) coating to thesecond portion of the plurality of nanofibers.